Endogenous neuropeptides constitute a growing list of biologically important molecules with both central and peripheral sites of action and loci of synthesis. In spite of the obvious importance of biologically-active peptides in regulating both endocrine and neural events, lacking is a detailed evaluation of the effects of ethanol on even a single neuropeptide system. Since the administration of ethanol is known to alter certain regulatory aspects of the hypothalamic-pituitary-adrenal axis (HPAA) and since the integrity of this system depends on the synthesis and secretion of specific regulatory neuropeptides at the hypothalamic (e.g., corticotropin-releasing hormone (CFR); vasopressin) and pituitary gland (e.g., beta endorphin (BE); ACTH) level, we have been evaluating the impact of ethanol on the HPAA as a model system in vivo and in vitro. Realizing the necessity of understanding the direct versus indirect effects of ethanol at the cellular level, we have been working with AtT-20 cells, corticotropes, and melanotropes in culture and ethanol- exposed intact male rats. It has been possible to study the effects of ethanol on such primary signal transduction systems as the adenylate cyclase (AC)/cyclic (c) AMP system and the phosphoinositide protein kinase C system. It is envisioned that the exploration of each of the component parts of the HPAA (i.e., CNS, pituitary and adrenal gland) independent of one another and the subsequent intergration of results from the intact animal will enable one to profile the acute, chronic, direct and indirect effects of ethanol at the cellular and subcellular level, as well as the primary versus secondary sites of ethanol-induced perturbations of the HPAA. Since neuroendocrine cells are continuously synthesizing and secreting products, our studies in their broadest sense are designed to understand the effects of ethanol on stimulus-secretion-synthesis coupling in secretory cells. To date our investigations have yielded a variety of information.